Viral hemorrhagic fever (VHF) refers to a group of illnesses that are caused by members of four families of viruses. These viruses can cause life-threatening disease with signs of bleeding under the skin, in internal organs, or from various body orifices. Severe cases may also show shock, nervous system malfunction, coma, delirium, seizures and renal failure. Some VHF agents have been suspect for abuse in biowarfare/bioterrorism. Members of the family Flaviviridae are among the viral agents that cause VHF. Viruses in this family are all enveloped positive-sense RNA viruses with many similar features in their genome structure and replication cycle. There is no specific treatment for any of the agents that cause VHF, although ribavirin has been effective in treating some cases of VHF and shows some activity against a number of RNA viruses including YFV.This application is in response to the challenge to develop specific treatment modalities for these diseases. We plan to develop cell-based assays for testing and screening of compounds with antiviral activity against certain flaviviruses. These assays will be based on cell lines that harbor a constitutively replicating subgenomic replicon and are modeled on a prototype system developed for hepatitis C virus. Our approach is applicable to a number of viruses that cause viral hemorrhagic fever such as category A bioterrorism agents (tick-borne encephalitis virus, Kyasanur Forest disease virus, Omsk hemorrhagic fever virus, etc.) and category C agents (yellow fever virus, Dengue virus, etc.).